(4-Or 5-nitroimidazolyl)-imidazole compounds

ABSTRACT

4- or 5-nitro-imidazoles of the formula I wherein one of the radicals R1 and R2 is hydrogen or lower alkyl and R2 is the nitro group or R1 is the nitro group and R2 is hydrogen or lower alkyl, R3 is lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylsulphonyl-lower alkyl, dilower alkylamino-lower alkyl, lower alkylene-amino-lower alkyl, lower oxaalkyleneamino-lower alkyl, lower thiaalkyleneamino-lower alkyl or lower azaalkyleneamino lower alkyl, R4 is oxo or thioxo and R5 is a phenyl radical which optionally has one, two or more substituents, an optionally substituted furyl, thienyl, pyrrolyl, indolyl, oxazolyl, thiazolyl, thiadiazolyl, 4,5-dihydrothiazolyl-(2), tetrahydro-thiazolyl-(2), pyrazolyl, indazolyl, imidazolyl-(5), imidazolyl-(4), pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5- or 1,2,4-triazinyl, pyrrolidinyl, pyrazolinyl, indolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidyl, morpholinyl, thiazinyl, thiomorpholinyl or piperazinyl radical, an optionally C-lower alkylated pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, N&#39;&#39;-lower alkyl-piperazino, N&#39;&#39; Beta -hydroxyethylpiperazino or pyridinium radical and R6 and R7 independently of one another denote hydrogen or lower alkyl or conjointly form the missing part of a fused benzene nucleus which is optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or nitro, as well as their S-oxides, sulphones N-oxides and/or acid addition salts thereof, which are useful as agents against schistosomes, filaria, trichomonades, bacteriae, and/or amoebae.

United States Patent [191 Ilvespiiii Oct. 21, 1975 [54] (4- ORS-NITROIMIDAZOLYL)-IMIDAZOLE COMPOUNDS [73] Assignee: Ciba-GeigyCorporation, Ardsley,

22 Filed: 1311.31, 1973 21 Appl.No.: 328,816

[30] Foreign Application Priority Data Feb. 8, 1972 Switzerland 1810/72Dec. 27, 1972 Switzerland 18867/72 [51] Int. Cl. ..C07D 401/14; C07D403/02; CO7D 413/14; C07D 417/14 [58] Field of Search 260/309.6

[56] References Cited UNITED STATES PATENTS 3,770,763 11/1973 Cusic etal. 260/3()9.5 FOREIGN PATENTS OR APPLICATIONS 2,135,253 12/1972 France260/309.6

Primary Examiner-Natalie Trousof Attorney, Agent, or Firm-Joseph G.Kolodny; John J. Maitner; Theodore O. Groeger [57] 7 ABSTRACT 4- orS-nitro-imidazoles of the formula I wherein one of the radicals R and Ris hydrogen or lower alkyl and R is the nitro group or R is the nitrogroup and R is hydrogen or lower alkyl, R is lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, lower alkylsulphonyl-lower alkyl,di-lower alkylaminolower alkyl, lower alkylene-amino-lower alkyl, loweroxaalkyleneamino-lower alkyl, lower thiaalkyleneamino-lower alkyl orlower azaalkyleneamino lower alkyl, R is 0x0 or thioxo and R is a phenylradical which optionally has one, two or more substituents, anoptionally substituted fury], thienyl, pyrrolyl, indolyl, oxazolyl,thiazolyl, thiadiazolyl, 4,5-dihydrothiazolyl-( 2),tetrahydro-thiazolyl-(2). pyrazolyl, indazolyl, imidazolyl-(S),imidazolyl-(4), pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 135- or1,2.4-triazinyl, pyrrolidinyl, pyrazolinyl, indolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidyl, morpholinyl, thiazinyl,thiorno'rpholinyl or piperazinyl radical, an optionally C-loweralkylated pyrrolidino, piperidino, morpholino, thiomorpholino,piperazino, N-lower alkyl-piperazino, N"-B-hydroxyethyl-piperazino orpyridinium radical and R and'R, independently of one an other denotehydrogen or lower alkyl or conjointly form the missing part of a fusedbenzene nucleus which is optionally substituted by lower alkyl, loweralkoxy, halogen, trifluoromethyl and/or nitro, as well as theirS-oxides, sulphones N-oxides and/or acid addition salts thereof, whichare useful as agents against schistosomes, filaria, trichomonades,bacteriae, and/or amoebae.

4 Claims, No Drawings 1 (4-OR S-NITROIMIDAZOLYL )-IMHDAZOLE COMPOUNDSThe sub ect of the invention are new 4- or nitroimidazoles of theformula I wherein one of the radicals R and R is hydrogen or lower alkyland the other is the nitro group, R is hydrogen or optionallysubstituted lower alkyl, R is oxo or thioxo, R is hydrogen, optionallysubstituted lower alkyl or phenyl, acyl or a heterocyclic radical and Rand R independently of one another denote hydrogen or lower alkyl orconjointly denote the missing part of an optionally substituted fusedbenzene nucleus, and processes for their manufacture.

In the preceding and following text, a lower radical such as, forexample, a lower alkyl radical, is to be understood as a radical, forexample an alkyl radical, which contains not more than 8 and especiallynot more than 4, carbon atoms.

Lower alkyl is hence straight-chain or branched octyl, heptyl, hexyl,pentyl or in particular butyl or propyl, bonded in any desired position,or especially ethyl or methyl. Substituted lower alkyl is in particularlower alkyl which carries one or more substituents which can beidentical or different. As such substitutents there should in particularhe mentioned: aryl, above all optionally substituted phenyl, hydroxygroup, mercapto group, halogen, above all fluorine, chlorine or bromine,lower alkoxy, above all butoxy, propoxy, isopropoxy or especially ethoxyor methoxy, alkylmercapto, such as, for example, the mercapto groupsubstituted by lower alkyl, above all butylmercapto, propylmercapto,isopropylmercapto or especially ethylmercapto or methylmercapto, thefree amino group, secondary amino groups, above all optionallysubstituted anilino groups or lower alkylamino groups, such asbutylamino, propylamino, isopropylamino or especially ethylamino ormethylamino, the free amino group, or tertiary amino groups, such asoptionally substituted N-lower alkylanilino groups, for example theN-butyl-, N- propyl-, N-isopropylor especially N-ethylor N-methyl-anilino group or above all di-lower alkylamino groups, forexample dibutylamino, diisobutylamino, dipropylamino, diisopropylamino,ethylmethylamino or especially diethylamino or dimethylamino, and alsoespecially alk-yleneamino and oxaalkyleneamino, azaalkyleneamino orthiaalkyleneamino groups, such as the optionally C-methylatedpyrrolidino, piperidino, morpholino, thiomorpholino,2,6-dimethylthiomorpholino, piperazino, N'-methylpiperazino orN-B-(hydroxyethyl)-piperazino group, or sulphonyl groups, such asarylsulphonyl groups, for example optionally substitutedbenzenesulphonyl groups, or alkanesulphonyl groups, above all loweralkanesulphonvl groups. for exthe methanesulphonyl or ethanesulphonylample group.

Acyl is, in particular, the radical ofa carboxylic acid derived from anaromatic or aliphatic hydrocarbon radical, above all an aroyl group,such as, for example, an optionally substituted benzoyl group, or analkanoyl group, especially a lower alkanoyl group, such as, for example,valeroyl, isovaleroyl, pivaloyl, butyryl, isobutyryl, propionyl, formyland especially acetyl, or the radical of an organic sulphonic acid,above all of an ar omatic sulphonic acid such as, for example, ofbenzenesulphonic acid, toluenesulphonic acid or bromobenzenesulphonicacid, or of an aliphatic sulphonic acid, for example of methanesulphonicacid or ethanesulphonic acid.

By optionally substituted phenyl or benzoyl or an optionally substitutedfused benzene ring there are to be understood both these groupsthemselves and also phenyl groups, benzoyl groups and fused benzenerings substituted by one, two or more than two identical or differentsubstituents, such as lower alkyl, lower alkoxy, halogen, above allchlorine or bromine, nitro and- /or trifluorome thyl.

Possible halogen atoms are especially fluorine or bromine atoms andabove all chlorine atoms.

A heterocyclic radical is especially a heteroaromatic or heteroaliphaticradical. Heterocyclic radicals are bonded via an atom which is a memberof a heterocyclic ring.

A heteroaryl radical R is, for example, a mononuclear or polynuclearradical of aromatic character which contains, as a constituent, at leastone het erocyclic ring of aromatic character possessing a hetero-atom.Suitable hetero-atoms are, for example, oxygen, sulphur and/or nitrogenatoms.

Suitable radicals of this nature are, for example, radicals possessingat least one five-membered ring containing at least one hetero-atom,especially one of those mentioned above, such as furyl, benzo[b]furyl,thienyl, benzo[b]-thienyl, pyrrolyl, indolyl, oxazolyl, thiazolyl,isooxazolyl, isothiazolyl, pyrazolyl, 3H-pyrazolyl, indazolyl, andimidazolyl radicals, above all 2-imidazolyl radicals which can also besubstituted in the 1-position, especially by acyl, lower alkyl orsubstituted lower alkyl, in one of positions 4 or 5 by lower alkyl andin the other of the positions mentioned by lower alkyl or by the nitrogroup, and also furazanyl and triazolyl radicals, such as, for example,lH- or 2H-l,2,4-triazolyl radicals, thiadiazolyl radicals and tetrazolylradicals, as well as radicals possessing at least one six-membered ringwhich contains at least one hetero-atom, especially one of thosementioned above, such as pyridyl, quinolyl, isoquinolyl, acridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, phenazinyl, 1,3,5-and 1,2,4- triazinyl radicals.

The heterocyclic radicals of aromatic character can have one, two ormore substituents but are preferably unsubstituted.

Possible substituents on carbon atoms of the heteroaryl radicalsmentioned are especially lower alkoxy groups, such as methoxy, ethoxy,propoxy and butoxy groups, trifluoromethyl groups, optionallysubstituted amino groups or nitro groups, and especially hydroxylgroups, halogen atoms, such as fluorine, chlorine and bromine atoms, andabove all lower alkyl radicals, such as methyl, ethyl, propyl andisopropyl radicals, straight and branched butyl, pentyl and hexylradicals bonded in any desired position, as well as phenyl radicalsoptionally substituted by lower alkyl, lower alkoxy, halogen ortrifluoromethyl groups, and mercapto groups.

Optionally substituted amino groups are, for example, monoand di-loweralkylamino groups as well as acylamino groups and N-acyl-N-loweralkylarnino groups, such as methyl-, ethyl-, dimethyl-, diethyl-, loweralkanoyl-, for example acetyl-, N-lower alkanoyl- N-lower alkyl forexample N-acetyl-N-methyl-, benzoyland N-benzoyl-N-methyl-amino groups.

In heterocyclic radicals which carry a hydrogen atom on a ring nitrogenatom, the hydrogen atom can also be replaced by lower alkyl radicals oracyl radicals, especially benzoyl radicals which are optionallysubstituted, for example substituted as indicated above for the arylradicals, and above all lower alkanoyl radicals, for example propionyl,butyryl and especially acetyl radicals.

ln heterocyclic radicals, oxidisable hetero-atoms can also be present inthe form of their oxides. Thus, in particular, sulphur atoms can beS-oxidised or S-dioxidised and above all nitrogen atoms can beN-oxidised.

The free valency of the heterocyclic radicals of aromatic character inparticular starts from a C atom belonging to the aromatic system.

A heteroaliphatic radical R is, for example, a monocyclic or polycyclicradical of aliphatic character which contains, as a constituent, atleast one heterocyclic ring of aliphatic character possessing at leastone heteroatom, such as one of those mentioned above.

Suitable radicals of this nature are, for example, radicals possessingat least one five-membered ring which contains at least one hetero atom,especially one of those mentioned above, such as tetrahydrofuryl,tetrahydrothienyl, pyrrolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl,4,5-alkylenethiazolyl-(2), 4,5-dihydrothiazolyl, tetrahydrothiazolyl,imidazolinyl and imidazolidinyl radicals, as well as radicals possessingat least one six-membered ring which contains at least one hetero-atom,especially one of those mentioned above, such as pyranyl, for example2H- and 4H-pyranyl, tetrahydropyranyl, thiopyranyl, for example 2H- and4H- thiopyranyl, tetrahydrothiopyranyl, tetrahydropyridyl, for examplel,2,3,4-tetrahydropyridyl, piperidyl, l,2,3,4-tetrahydroquinolyl,oxazinyl, such as 2H-l,2-, 4H-l,2-, 6H-1,2-, 2l-l-1,3-, 4H-l,3- and4H-1,4- oxazinyl, morpholinyl, thiazinyl, for example 2H-l,3- thiazinyl,thiomorpholinyl and piperazinyl radicals.

The heteroaliphatic radicals can have one, two or more substituents butare preferably unsubstituted.

Possible substituents on carbon atoms of the heteroaliphatic radicalsmentioned are in particular alkoxy radicals, halogen atoms, hydroxylgroups and optionally substituted amino groups, such as those mentionedabove, and above all lower alkyl radicals, such as those mentionedabove.

Ring nitrogen atoms carrying a hydrogen atom can be substituted,especially as indicated above, and oxidisable hetero-atoms can bepresent in the form of their oxides, especially as indicated above.

The free valency of the heteroaliphatic radicals in particular startsfrom a C atom belonging to the hetero cyclic structure.

The new imidazoles possess valuable pharmacological properties. Thusthey show, in particular, actions against bacteria, especiallyGram-negative germs, protozoa and worms, such as trichomonades,schistosomes, coccidia, filaria and above all amoebae, as can be shownin animal experiments, for example on hamsters. The new imidazoles aretherefore usefull as agents against schistosomes, filaria,trichomonades, bacteria and especially against amoebae. Furthermore, thenew imidazoles can serve as starting products or intermediate productsfor the manufacture of other compounds, especially therapeuticallyactive compounds.

A preferred group is the group la of those compounds of the formula Iwherein one of the radicals R, and R is hydrogen or lower alkyl and theother is the nitro group, R is hydrogen, optionally substituted loweralkyl or acyl, R, is oxo or thioxo, R is hydrogen, optionallysubstituted lower alkyl or phenyl, acyl or a heteroaryl and R and Rindependently of one another denote hydrogen or lower alkyl orconjointly denote the missing part of an optionally substituted fusedbenzene nucleus.

A group to be singled out is the group lb of those compounds of theformula I wherein R, is hydrogen or lower alkyl and R is the nitro groupor R, is the nitro group and R is hydrogen or lower alkyl, R ishydrogen, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, monoordi-lower alkylamino-lower alkyl, alkyleneamino-lower alkyl, optionallyC-methylated morpholino-, thiomorpholinoor N'-methylpiperazinoloweralkyl, lower alkoxy-lower alkyl, halogeno-lower alkyl or loweralkylmercapto-lower alkyl, R, is oxo or thioxo, R has one of themeanings indicated for R is lower alkanoyl or benzoyl optionallysubstituted by lower alkyl, lower alkoxy, halogen, trifluoromethyland/or nitro or denotes a phenyl or Z-imidazolyl radical which isoptionally substituted by lower alkyl, lower alkoxy, halogen,trifluoromethyl and/or nitro and R and R independently of one anotherdenote hydrogen or lower alkyl or conjointly form the missing part of afused benzene nucleus which is optionally substituted by lower alkyl,lower alkoxy, halogen, trifluoromethyl and/or nitro.

A further group to be singled out is the group lc of those compounds ofthe formula I wherein R, is hydrogen or lower alkyl and R is the nitrogroup or R, is the nitro group and R is hydrogen or lower alkyl, R, islower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, loweralkylsulphonyl-lower alkyl, di-lower alkylamino-lower alkyl, loweralkyleneamino-lower alkyl, lower oxaalkyleneamino-lower alkyl, lowerthiaalkyleneamino-lower alkyl or lower azaalkyleneamino-lower alkyl, R,is oxo or thioxo and R is a phenyl radical which optionally has one, twoor more substituents, an optionally substituted furyl, thienyl,pyrrolyl, indolyl, oxazolyl, thiazolyl, thiadiazolyl,4,5dihydro-thiazolyl-(2), tetrahydro-thiazolyl-(2), pyrazolyl,indazolyl, imidazolyl-(S), imidazolyl-(4), pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, 1,3,5- or 1,2,4- triazinyl, pyrrolidinyl,pyrazolinyl, indolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidyl, morpholinyl, thiazinyl, thiomorpholinyl or piperazinylradical, an optionally C-lower alkylated pyrrolidino, piperidino,morpholino, thiomorpholino, piperazino, N-lower alkyl-piperazino,N-,B-hydroxyethyl-piperazino or pyri dinium radical and R and Rindependently of one another denote hydrogen or lower alkyl orconjointly form the missing part of a fused benzene nucleus which isoptionally substituted by lower alkyl, lower alkoxy,

halogen, trifluoromethyl and/or nitro, as well as their S-oxides,sulphones and N-oxides.

A group which is especially suitable is the group ld of those compoundsof the formula I wherein R, is hydrogen or lower alkyl and R is thenitro group or R, is the nitro group and R is hydrogen or lower alkyl, Rhydrogen, lower alkyl, hydroxy-lower alkyl, above all Z-hydroxypropyl, 1or 2-hydroxyethyl or hydroxymethyl, amino-, mono-, or di-loweralkylamino-, pyrrolidino-, piperidino-, morpholino-, thiomorpholinoor Nmethylpiperazino-lower alkyl, above all -methyl or -ethyl, chloroorbromo-lower alkyl, above all -ethyl, or lower alkoxy-lower alkyl, aboveall methoxyor ethoxylower alkyl, R is x0 or thioxo, R, has one of themeanings indicated for R or is a radical of the formula wherein R, ishydrogen or lower alkyl, R has one of the meanings indicated for R or islower alkanoyl or aroyl, such as benzoyl optionally substituted by loweralkyl, lower alkoxy, halogen, trifluoromethyl and/or nitro, R ishydrogen or the nitro group and R and R independently of one anotherdenote hydrogen or lower alkyl or conjointly form the missing part of afused benzene nucleus which is optionally substituted by lower alkyl,lower alkoxy, halogen, trifluoromethyl and/or nitro.

Amongst the abovementioned compounds of the group ld there should inturn be singled out the group le, wherein R is a radical of the formulathe symbols R,, R R and R have the meanings indicated for the group Idand R and R denote hydrogen or conjointly denote the missingpart of afused benzene nucleus.

A further group which is particularly suitable is the group If of thosecompounds of the formula I wherein R, is hydrogen or lower alkyl and Ris the nitro group or R, is the nitro group and R is hydrogen or loweralkyl, R is hydroxy-lower alkyl or lower alkyl, R, is 0x0 or thioxo andR is hydrogen, lower alkyl, hydroxylower alkyl, loweralkoxy-lower alkyl,propionyl, butyryl, acetyl, formyl, phenyl, 0-, mor p-fluorophenyl, 4-thiazolyl, 2-thiazolyl, 4,5-dimethylthiazolyl-(2), 5,6-dihydro-4H-cyclopenta-thiazolyl-(2), 5-amino-l,3,4- thiadiazolyl-(Z),4,5-dihydro-thiazolyl-(2), tetrahydrothiazolyl-(Z),4-acetyl-thiazolyl-(2), 5-acetyl-thiazolyl- 6 (2),5-methylsulphonyl-thiazolyl-(2), pyridyl-(2), Pyridyl-(3), pyridyl-(4),4,6-dimethyl-pyridyl-(2), 3,5-dimethylpyridyl-(2), PyFimidinyI-(Z),pyrimidinyl- (5), 2,6-dihydroxy-pyrimidinyl-(4), pyrimidinyl-(S),4,6-dimethyl-pyrimidinyl-(2), Pyrrolidinyl-(Z), piperidyl-'(3),imidazolyl-(2), imidazolyl- (4), imidazolyl-(S), 1,3,4-thiadiazolyl-(2),S-methyll,3,4-thiadiazolyl(2), S-ethyl-l,3,4-thiadiazolyl-(2) or anoptionally C-lower alkylated pyrrolidino, piperidino, morpholino,thiomorpholino, for example 2,6-dimethyl-thiomorpholino, piperazino,N-lower alkylpiperazino, N'-B-hydroxyethylpiperazino or pyridiniumradical and R and R independently of one another de- V note hydrogen orlower alkyl or conjointly form the missing part of a fused benzenenucleus which is optionally substituted by lower alkyl, lower alkoxy,halogen, trifluoromethyl and/or nitro, as well as their S- oxides,sulphones and N-oxides.

However, a group which is suitable above all is the group lg of thosecompounds of the formula I wherein R, is hydrogen or lower alkyl and Ris the nitro group or R, is the nitro group and R is hydrogen or loweralkyl, R is oxo or thioxo, R and R independently of one another arehydrogen, lower alkyl, 2-hydroxyethyl or Z-hydroxypropyl, hydroxymethyl,2-di-lower alkylaminoethyl or 2-di-lower alkylaminopropyl or diloweralkylaminomethyl and R can also be lower alkanoyl, and R and Rindependently of one another denote hydrogen or lower alkyl orconjointly form the missing part of a fused benzene nucleus.

Of the abovementioned compounds of the group lg there should in turn besingled out the group Ih,

wherein R, is hydrogen or methyl and R is the nitro group or R, is thenitro group and R is hydrogen or methyl, R is oxo or thioxo, R and Rindependently of one another denote lower alkyl, hydroxymethyl orhydroxyethyl and R can also be lower alkanoyl and R and R are hydrogen.

However, a group which is suitable above all is also the group li ofthose compounds of the formula I wherein R, is hydrogen or methyl and Ris the nitro group or R, is the nitro group and R is hydrogen or methyl,R is 2-hydroxyethyl or methyl, R is 0x0 or thioxo and R is hydrogen,methyl, hydroxymethyl, propionyl, acetyl, formyl, phenyl,p-fluorophenyl, thiazolyl- (2), 4,5-dimethyl-thiazolyl-(2),5,6-dihydro-4H- cyclopenta-thiazole-(2), 5-acetyl-thiazolyl-(2), 5-methylsulphonyl-thiazolyl-(2), pyridyl-(2), 4,6-dimethylpyridyl-(Z),pyrimidinyl-(2), pyrimidinyl-(S), 4,6-dimethyl-pyrimidinyl-(2),2,4-dimethylpyrimidinyl-( 5 pyrrolidinyl-(Z), piperidyl-( 3imidazolyl-(Z), imidazolyl-(4), imidazolyl-(S), 1,3,4- thiadiazolyl-(Z),S-ethyll ,3,4-thiadiazolyl-(2) or a pyrrolidino, piperidino, morpholino,thiomorpholino, 2,-dimethyl-thiomorpholino, piperazino,N-methylpiperazino, N-B-hydroxyethylpiperazino or pyridinium radical andR and R are hydrogen, as well as their S- oxides, sulphones and Noxides.

However, a group which deserves very particular mention is the group ljof those compounds of the formula I wherein R, is hydrogen and R is thenitro group or R, is the nitro group and R is hydrogen, R is hydrogen orabove all lower alkyl with l4 carbon atoms, R, is 0x0 or above allthioxo, R is lower alkyl with 1-4 carbon atoms, above all methyl, orphenyl which is optionally substituted by methyl, methoxy, chlorine,bromine or trifluoromethyl but is above all unsubstituted2,4-dimethyland R and R denote hydrogen, in particular l-methyl- 3-(l-methyl--nitro-2-imidazolyl)-benzimidazol-2- (3H)-one, l-methyl-3-(l-methyl-5-nitro-2-imidazolyl)- benzimidazole-2-(3H)-thione,l-methyl-3-( l-methyl-S- nitro-Z-imidazolyl)-4-imidazolin-2-one and veryparticularly l-phenyl-3-( l-methyl-5-nitro-2-imidazolyl)-4-imidazoline-Z-thione, l-methyl-3-(1-methyl-4-nitro-2-imidazolyl)-4-imidazoline-2-thione and lmethyl-3-( lmethyl-5-nitro-2-imidazolyl)-4-imidazoline-2-thione.

The new 4- or S-nitroimidazoles of the formula I are obtained accordingto processes which are in themselves known.

Thus, for example, the new 4- or S-nitro-imidazoles can be manufacturedby condensing a compound of the formula ll I ll R2 N x with a compoundof the formula III or a tautomeric compound of the formula llla whereinR R R R R R and R have the indicated meanings, R is an oxygen atom orabove all a sulphur atom, Y is a metal atom, for example an alkali metalatom or alkaline earth metal atom or especially a hydrogen atom and X isa reactive etherified hydroxyl group, a free or etherified mercaptogroup, an ammonium group or especially a reactive esterified hydroxylgroup or a sulphonyl group.

A reactive etherified hydroxyl group is, for example, a hydroxyl groupetherified with an aromatic or aliphatic alcohol, above all with a loweraliphatic alcohol, such as an optionally substituted phenoxy group or analkoxy group, above all a lower alkoxy group, especially methoxy orethoxy.

An etherified mercapto group is, for example, an optionally substitutedphenylmercapto or benzylmercapto group or in particular a loweralkylmercapto group, such as the ethylmercapto or methylmercapto group.

An ammonium group is, in particular, a quaternary ammonium group, aboveall a tri-lower alkylammonium group, for examplel the trimethylammoniumor triethylammonium group or the cation of an aromatic nitrogen base,for example the pyridinium or quinolinium group.

A reactive esterified hydroxyl group is, in particular, a hydroxyl groupesterified by a strong inorganic or or-. ganic acid, above all ahydrogen halide acid, such as hydrochloric acid, hydrobromic acid orhydriodic acid, or an organic sulphonic acid, especially an aromaticsulphonic acid, for example benzenesulphonic acid,p-bromobenzenesulphonic acid or p-toluenesulphonic acid, or analkanesulphonic acid, above all a lower alkanesulphonic acid, forexample methanesulphonic acid, ethanesulphonic acid or an olefinicsulphonic acid, for example ethenesulphonic acid.

A sulphonyl group is especially a sulphonyl group derived from anorganic sulphonic acid, especially from an aromatic sulphonic acid, forexample benzenesulphonic acid, p-bromobenzenesulphonic acid orp-toluenesulphonic acid, from an alkanesulphonic acid, above all a loweralkanesulphonic acid, for example methanesulphonic acid orethanesulphonic acid, or from an olefinic sulphonic acid, for exampleethenesulphonic acid.

The reaction can be carried out in the usual manner. Thus, in thereaction of a compound of the formula II with a compound of the formulaIII or Illa, wherein Y is hydrogen, a basic condensation agent ispreferably present, or the compound of the formula III or Illa isreacted in the form of a salt, for example ofa metal salt, such as of analkali metal salt or alkaline earth metal salt, which is obtainable, forexample, from a compound of the formula III or Illa and a strong base,for example an amide, a hydrocarbon compound, an alcoholate, thehydroxide or especially the hydride of a metal, for example of an alkalimetal, such as of lithium, potassium or above all sodium, or of analkaline earth metal, such as of magnesium or calcium, or the metalitself, and can be used without isolation. Examples of basiccondensation agents are alkali metal hydroxides or alkaline earth metalhydroxides, such as sodium hydroxide, potassium hydroxide and calciumhydroxide, or organic tertiary nitrogen bases, such as trialkylamines,for example, triethylamine or trimethylamine, or aromatic nitrogenbases, for example pyridine or quinoline. It is furthermore alsopossible to use an excess of the compound of the formula III or llla,especially if R is not hydrogen. The reaction is advantageously carriedout at elevated temperature and/or in the presence of an inert solvent,especially of an inert polar solvent, for example of acetonitrile,dimethyl sulphoxide, tetramethylurea, of a higher-boiling ether, forexample of dioxane, diphenyl ether, diisopropyl ether or an ether ofethylene glycol, or of tetrahydrofurane, of water, of a higher alcohol,of one of the nitrogen bases mentioned or especially ofdimethylformamide.

When starting fromcompounds of the formula III or lIIa, wherein Y and Rdenote hydrogen it is possible,

'on suitably choosing the reaction conditions and using double molaramounts of a compound of the formula II, to obtain both 1-mono-(4- or5-nitro-2-imidazolyl)- 4-imidazolin2-ones or -thines and l,3-bis-(4- ornitro-2-imioazolyl)-4-imidazolin-2ones or -thiones of the formula I.

Furthermore, the new 4- or S-nitro-imidazoles can be obtained, forexample, if a compound of the formula IV wherein R,, R R R R and R havethe indicated meanings is isomerised.

The isomerisation can be carried out in the usual manner, for examplethermally. Preferably, this is done at an elevated temperature, forexample between 50 and 250C, and in the presence of a catalyst, such ascatalytic amounts of a halogen, especially of iodine, or of a basiccondensation agent, such as, for example of an alkali metal hydroxide oralkaline earth metal hydroxide, for example of sodium hydroxide,potassium hydroxide and calcium hydroxide, or of an alkali metal salt oralkaline earth metal salt of a compound of the formula III or Illa or ofan organic tertiary nitrogen base, such as ofa trialkylamine, forexample of triethyl amine or trimethylamine, or of an aromatic nitrogenbase, for example of pyridine or quinoline, especially of an alkalimetal hydride or alkali metal amide. The isomerisation is advantageouslycarried out in an inert solvent, preferably in an inert polar solvent,for example in acetonitrile, dimethylsulphoxide, tetramethylurea, ahigher-boiling ether, such as dioxane, diphenyl ether or diisopropylether, an ether of ethylene glycol or tetrahydrofurane, in water, ahigher alcohol, an organic tertiary nitrogen base, such as atrialkylamine, for example in triethylamine or trimethylamine, or anaromatic nitrogen base, for example in pyridine or quinoline.

In resulting compounds, substituents can be introduced, modified orsplit off, within the framework of the definition of the finalsubstances.

Thus, compounds of the formula I which contain a nitro group as theradical R can be rearranged in a surprising manner into thecorresponding 4- nitroimidazoles, that is to say those compounds of theformula I which contain a nitro group as the radical R Thisrearrangement takes place in a novel manner by the action of an alkaliiodide, especially of potassium iodide, preferably in a molar excess,and in the presence of an inert solvent, above all a solvent havingpolar functional groups, such as dimethylformamide, dimethylacetamide,dimethylsulphoxide, acetonitrile or hexamethylphosphoric acid triamide.

The rearrangement of R =nitro into R =nitro compounds of the formula Ican also be effected by the action of an iodide which corresponds to theradical R R 1, such as, for example, the action of methyl iodide oncompounds of the formula I which contain a methyl group as the Rradical. In this rearrangement, the unsubstituted nitrogen atom of theimidazole ring is quaternised. Thereafter the quaternised salt ispyrolysed. This rearrangement also takes place, for example, in thepresence of an inert solvent, preferably those described above.

Depending on the process conditions and the starting substances, thefinal substances are obtained in the free form or in the form of theiracid addition salts which is also included in the invention. Thus, forexample, basic, neutral or mixed salts, and if appropriate alsohemihydrates, monohydrates, sesquihydrates or polyhydrates thereof, canbe obtained. The acid addition salts of the new compounds can beconverted into the free compound in a manner which is in itself known,for example with basic agents, such as alkalis or ion exchangers. On theother hand, the resulting free bases can form salts with organic orinorganic acids. In particular, those acids are used for the manufactureof acid addition salts which are suitable for forming therapeuticallyusable salts. As examples of such acids there may be mentioned: hydrogenhalide acids, sulphuric acids, phosphoric acids, nitric acid, perchloricacid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids orsulphonic acids, such as formic acid, acetic acid, propionic acid,succinic acid, glycollic acid, lactice acid, malic acid, tartaric acid,citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvicacid; phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilicacid, p-hydroxybenzoic acid, salicylic acid or paminosalicyclic acid,embonic acid, methanesulphonic acid, ethanesulphonic acid,hydroxyethanesulphonic acid and ethylenesulphonic acid;halogenobenzenesulphonic acid, toluenesulphonic acid,naphthalenesulphonic acid or sulphanilic acid; methionine, tryptophane,lysine or arginine.

These or other salts of the new compounds such as, for example, thepicrates can also serve for the purification of the resulting free basesby converting the free bases into salts, isolating these and againliberating the bases from the salts. Because of the close relationshipsbetween the new compounds in the free form and in the form of theirsalts the free compounds are to be understood, in the preceding andfollowing text, where appropriate also to include the correspondingsalts in general sense and intended use.

The inventionalso relates to those embodiments of a process in which aprocess is stopped at any stage or in which a compound obtainable as anintermediate product at any stage is used as the starting product andthe missing steps are carried out, or in which a starting substance isused in the form of a salt and/or racemate or antipode or, inparticular, is formed under the reaction conditions.

Depending on the number of the asymmetrical C atoms and the choice ofthe starting substances and prodedures, the new comopunds can be in theform of racemate mixtures, racemates or optical antipodes.

Racemate mixtures can be separated into the pure racemates on the basisof the physico-chemical differences of the constituents in a knownmanner, for example by chromatography and/or fractional crystallisation.

The separation of racemates obtained into the optical antipodes can becarried out in a manner which is in itself known. Resulting racematescan, for example, be converted into esters of optically active acids or,preferably, into salts with optically active acids. Particularlycustomary optically active acids are, for example,

the D- and L- forms of tartaric acid,di-o-toluyltartaric acid,diacetyl-tartaric acid, 'malic acid, mandelic acid, camphoric acid,camphorsulphonic acid, bromocamphorsulphonic acid and quinic acid.

The resulting mixtures of diastereoisomeric salts are separated into theindividual salts on the basis of physi co-chemical differences, forexample in solubility, crystallisability and the like, and the opticallyactive antipodes are liberated from the salts. Furthermore, a resultingracemate in the salt form can be reacted with an optically active metalcomplex salt or a resulting racemate in the free form can be reactedwith an optically active metal complex hydroxide, and the less solubleproduct can be separated off and the optically pure compound liberated.Suitable optically active metal complexes are, for example, opticallyactive cobalt nitrate complex compounds.

It is furthermore also possible to separate racemates obtained into theoptically active antipodes by fractional crystallisation, if appropriatefrom an optically active solvent, or by chromatography, especially thinlayer chromatography, on an optically active carrier, or with the aid ofmicroorganisms. Mixtures of diastereoisomeric compounds are separatedinto the pure isomeric compounds in the customary manner on the basis oftheir physico-chemical differences, such as those of solubility, boilingpoints and the like, for example by fractional crystallisation ordistillation. Herein, the pharmacologically more active pure isomer,especially the more active or less toxic antipode, is advantageouslyisolated.

According to the invention it is, however, also possible to obtain theend products in the form of the pure racemates or optical antipodes byemploying starting substances containing one or more asymmetrical Catoms in the form of the pure racemates or optical antipodes.

The starting substances are known or can, if they are new, be obtainedaccording to methods which are in themselves known. Appropriately, thosestarting substances are used for carrying out the reactions according tothe invention as lead to the initially particularly mentioned groups offinal substances and particularly to the final substances which havebeen especially described and singled out.

Thus, the 4- or S-nitroimidazoles of the formula IV which have beenmentioned as starting substances can be obtained, for example, bycondensing a compound of formula ll wherein R R R R R R R and X have theindicated meanings.

The reaction can be carried out in the usual manner. Thus, for example,when starting from starting substances wherein X is one of the radicalsX which have been mentioned, the reaction is preferably carried out inthe presence of a basic condensation agent, or the compound of theformula Illa or III is reacted in the form of a N-metal derivative, suchas, for example, an alkali metal derivative, which is obtainable, forexample, from a compound of the formula III or Illa and a strong base,for example an amide, a hydrocarbon compound, an alcoholate, thehydroxide or especially the hydride of an alkali metal, such as oflithium, potassium or above all sodium, or from this metal itself, andcan be used without isolation. Examples of basic condensation agents arealkali metal hydroxides or alkaline earth metal hydroxides, such assodium, potassium and calcium hydroxide or organic tertiary nitrogenbases, such as trialkylamines, for example triethylamine ortrimetheylamine, or aromatic nitrogen bases, for example, pyridine orquinoline. Advantageously, the reaction is carried out at elevatedtemperature and/or in the presence of an inert solvent, especially aninert solvent with polar groups, for example acetonitrile,dimethylsulphoxide, dimethylformamide, tetramethylurea, a higherboilingether, such as diphenyl ether, diisopropyl ether and ethers of ethyleneglycol, water, a higher alcohol, one of the nitrogen bases mentioned orespecially tetrahydrofurane or dioxane.

Depending on the starting substances used and the process conditions,the 4- or S-nitroimidazoles according to the invention of the formula Iare also obtained alongside the 4- or S-nitroimidazoles of the formulal\/ which have been mentioned as starting substances.

The yield of these final substances according to the invention can beincreased or reduced by suitable choice of the reaction conditions.Additionally it is generally not necessary to remove these substancesbefore carrying out the isomerisation reaction which has been described.

The new compounds can be used, for example, in the formof pharmaceuticalpreparations in which they are present in the free form or optionally inthe form of their salts, especially of the therapeutically usable salts,mixed with a pharmaceutical, organic or inorganic, solid or liquidexcipient which is suitable, for example,

(III 'a) for enteral or parenteral administration. Suitable substancesfor forming the ex'cipient are those which do not react with .the newcompounds such as, for example, water, gelatine, lactose, starch,stearyl alcohol, magnesium stearate. talc, vegetable oils, benzylalcohols, gum. propylene glycols, white petroleum jelly or other knownmedicinal excipients. The pharmacuetical preparations can, for example,be in the form of tablets, dragees, capsules or suppositories or in aliquid form, as solutions (for example as an elixir or syrup),suspensions or emulsions. If appropriate, they are sterilised and/orcontain auxiliaries, such as preservatives, stabilisers, wetting agentsor emulsifiers, solubilising agents or salts for regulating the osmoticpressure or buffers. They can also contain other therapeuticallyvaluable substances. The pharmaceutical preparations are obtainedaccording to customary methods. The dosage of the new compounds can varydepending on the com pound and on the individual requirements of thepatient. The customary daily dose for a warm-blooded an imal weighingapprox. 75 kg is between about 0.25 and 1.0 g.

The new compounds can also be used in veterinary medicine, for examplein one of the abovementioned forms or in the form of feedstuffs or ofadditives to animal fodder. Here, for example, the customary extendersanddiluents or feedstuffs are used.

Theinvention is described in more detail in the examples which follow.

.EXAMPLE 1 A solution of 11.4 g of 2-mercapto-l-methylimidazole in 60 mlof dimethylformamide is added dropwise over the course of minutes to asuspension of 4.8 g of 50 percent strength sodium hydride in 100 ml ofdimethylformamide at to C, whilst stirring. The resulting solution isthen added dropwise over the course of 30 minutes to a solution of 20.5g of 1- methyl-2-methylsulphonyl-5-nitro-imidazole in 80 ml ofdimethylformamide at 20 to 30C whilst stirring. Thereafter the reactionmixture is stirred for a further hour at 100C and is evaporated. Theevaporation residue is extracted by shaking with 200 ml of methylenechloride and 200 ml of water and the methylene chloride extract isseparated off, washed with 50 ml of water, dried over anhydrousmagnesium sulphate and evaporated. After two recrystallisations fromethyl acetate the evaporation residue yields pure 1-methyl-2-l-methyl-S-nitro-Z-imidazolyl)-mercapto]-imidazole of melting point123124C.

The combined mother liquors of the crystallisation are evaporated andseparated on a chromatography column of 50 mm diameter, filled with 550g of silica gel. Elution is carried out with methylene chloride andfractions of 600 ml each are collected. The 17th to 24th fraction arecombined and evaporated and the residue is recrystallised from 85 ml ofabsolute ethanol. Pure 1-methyl-3-(1-methyl-5-nitro-2-imidazolyl)-4-imidazoline-Z-thione of the formula and of melting point ll81C is thusobtained.

The 1-methyl-2-[(1-methyl-5-nitro-2-imidazolyl)- mercapto]-imidazoleconstituents still present on the column can be eluted with chloroformand be combined with the main quantity, after evaporation.

EXAMPLE 2 A solution of 12.0 g of 1-methyl-2-[( l-methyl-S-nitro-2-imidazolyl)-mercapto]-imidazole in 80 ml of dimethylformamide istreated with 0.3 g of 50 percent strength sodium hydride and heated to100C for 5 hours whilst stirring. Thereafter the reaction mixture isevaporated and the evaporation residue is taken up in ml of ethylenechloride. The resulting solution is washed five times with 50 ml ofwater at a time, dried over anhydrous magnesium sulphate and evaporated,and chromatographed on a column of 40 mm diameter filled with 300 g ofsilica gel. Elution is carried out with methylene chloride and fractionsof 600 ml are collected. The 9th to 12th fraction are combined andrecrystallised from 200 ml of ethanol. Pure l-methyl-3- (l-methyl-S-nitro-2-imidazolyl)-4-imidazoline-2- thione of melting point l80-18 1C,which is identical with the product obtained in Example 1, is thusobtained.

EXAMPLE 3 A solution of 7.5 g of l-phenyl-2-[( l-methyl-S-nitro-2-imidazolyl)-mercapto]-imidazole in 75 ml of dimethylformamide istreated with 0.2 g of 50 percent strength sodium hydride and heated to90-l00C for 20 hours whilst stirring. Thereafter the reaction mixture isevaporated and the evaporation residue is taken up in 150 ml of ethylenechloride and extracted by shaking five times with 50 ml of water at atime. The ethylene chloride extract is dried with anhydrous magnesiumsulphate and evaporated, and the evaporation residue is chromatographedon a column of 40 mm diameter filled with 300 g of silica gel. Elutionis carried out with methylene chloride and fractions of approx. 500 mlare collected. Fractions No. 12-l5 are combined and recrystallised from400 ml of alcohol. l-Phenyl-3-(1-methyl-5-nitro-2-imidazolyl)-4-imidazoline-2-thione of the formulaEXAMPLE 4 11.5 g of l-methyl-3-( l-methyl-5='nitro-2-imidazolyl)-4-imidazoline-2-thione, 30 g of ptassium iodide and ml ofdimethylformamide are heated under reflux for 15 hours. After cooling,the reaction mixture is treated with 1,000 ml of water and the productwhich has precipitated is filtered off and washed first with water andthen with isopropanol. The crude product thus obtained, which melts at236238C, is recrystallised from 225 ml of Z-ethoxyethanol. l- Methyl-3-(l-methyl-4-nitro-2-imidazolyl)-4- imidazoline-Z-thione of the formula Ti.i l 4 Y and of melting point 24l243C is thus obtained.

EXAMPLE 5 Tablets containing 250 mg of active substance are manufacturedin the customary manner, for example to have the following compositionper tablet:

Composition -Mcthy|-3-( l-methyl-5-nitro 2-imidazolyl )-4-imidnzolinc-Z-thinc 250 mg Lactose 36 mg Wheat starch 100 mg Colloidalsilica 16 mg Talc 16 mg Magnesium stcurute 2 mg MANUFACTURE 1-Methy|-3-(l-methyl--nitro-2-imidazolyl)-4- imidazoline-2-thione is mixed with thelactose, a part of the wheat starch and colloidal silica and the mixtureis rubbed through a sieve, whereby a powder mixture is obtained. Afurther part of the wheat starch is worked into a paste with a five-foldamount of water on a water-bath and the powder mixture is kneaded withthis paste until a slightly plastic mass has been produced.

The plastic mass is forced through a sieve of approx. 3 mm mesh widthand dried, and the dry granules are again forced through a sieve.Thereafter the remaining wheat starch, talc and magnesium stearate aremixed in and the resulting mixture is pressed to give tablets weighing420 mg (and having a breaking notch).

What I claim is:

1. An imidazole compound of the formula wherein one of R and R ishydrogen or lower alkyl and the other is nitro, R is hydrogen, loweralkyl, hydroxy-lower alkyl, lower alkoxy alkyl, R is thioxo, R ishydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,phenyl or mono-substituted phenyl substituted by lower alkyl, loweralkoxy, halogen or trifluoromethyl, and R and R, independently of oneanother denote hydrogen or lower alkyl, or a therapeutically acceptableacid addition salt thereof.

2. l-Phenyl-3-( l-methyl-S -nitro-2-imidazolyl)-4- imidazoline-Z-thioneor a therapeutically acceptable acid addition salt thereof.

3. l-Methyl-3-( l-methyl-4-nitro-2-imidazolyl)-4- imidazoline-Z-thioneor a therapeutically acceptable acid addition salt thereof.

4. l-Methyl-3-( l-methyl-5-nitro-2-imidazolyl )-4- imidazoline-Z-thioneor a therapeutically acceptable acid addition salt thereof.

1. AN IMIDAZOLE COMPOUND OF THE FORMULA 2.1-Phenyl-3-(1-methyl-5-nitro-2-imidazolyl)-4-imidazoline-2-thione or atherapeutically acceptable acid addition salt thereof. 3.1-Methyl-3-(1-methyl-4-nitro-2-imidazolyl)-4-imidazoline-2-thione or atherapeutically acceptable acid addition salt thereof. 4.1-Methyl-3-(1-methyl-5-nitro-2-imidazolyl)-4-imidazoline-2-thione or atherapeutically acceptable acid addition salt thereof.